Abstract
Background: The aim of this study was to characterize changes in outcome following hepatectomy for hepatocellular carcinoma (HCC) over a 30-year period. Patients and Methods: The clinical records of 372 patients who underwent a macroscopic curative hepatectomy for treatment of HCC between 1980 and 2009 were retrospectively examined. Patients were divided into two groups: an early group (1980-2000) and a late group (2001-2009). The relationship between the chronological treatment period and the surgical outcomes was investigated. Results: The disease-free survival (DFS) was comparable between the early and late groups (at 5 years: 30.3% vs. 31.2%, p=0.526), however, the overall survival (OS) of the late group was significantly better than the one of the early group (at 5 years: 80.1% vs. 50.4%, p<0.001), with this being an independent prognostic factor. Among the 148 patients who underwent transarterial chemoembolization (TACE) for initial hepatic recurrence, the OS after initial recurrence of the late group was significantly better than that of the early group (p=0.002). The OS after initial recurrence was significantly better in patients who underwent repeat hepatectomy than in those who underwent TACE (p=0.044). Conclusion: The results of hepatectomy for HCC have improved over time by use of various combination therapies after initial HCC recurrence. A repeat hepatectomy may be an acceptable treatment option for HCC recurrence in selected patients.
- Hepatocellular carcinoma
- hepatectomy
- transarterial chemoembolization
- repeat hepatectomy
- long-term survival
Liver resection is a widely accepted treatment method providing the chance of long-term survival for most patients with resectable hepatocellular carcinoma (HCC), with low morbidity and mortality (1, 2). Several studies have shown that patients who undergo hepatic resection for HCC have better survival results (3, 4). However, the high incidence of postoperative recurrence, which is caused by the potential for liver metastasis or carcinogenesis in the cirrhotic liver, remains a crucial problem (2, 5).
During the 20th century, non-surgical therapeutic options for HCC, such as percutaneous ethanol injection therapy (PEIT) and percutaneous radiofrequency ablation (RFA), have been widely performed, and these local ablation therapies yielded survival results similar to the results of surgery for the treatment of small HCC (6). Furthermore, the results of transarterial chemoembolization (TACE) have been improved by the technique of super-selective catheterization in the last quarter-century (7, 8). Although the safety of liver resection has also improved in recent years, hepatectomy is limited in its ability to prevent intrahepatic metastasis and reduce the frequency of multicentric carcinogenesis (5). When considering the management of HCC, it is important to clarify how the survival of patients with HCC has been prolonged in recent years and which treatment modality contributes most to improving survival after recurrence of HCC.
The aim of this study was to characterize changes in surgical outcomes following hepatectomy for the treatment of HCC at a single center over a 30-year period and to determine whether there was a significant improvement in the long-term outcomes of hepatic resection for the treatment of HCC in the 21st century compared with the 20th century. Moreover, we investigated which treatment modality contributes most to the improvement of survival after HCC recurrence.
Patients and Methods
Patients. In total, 372 patients underwent macroscopic curative hepatectomy for the treatment of HCC between 1980 and 2009 at the Department of Surgery, Division of Digestive Surgery, Kyoto Prefectural University of Medicine. All these patients were analyzed in this study. Patients were divided into two groups: an early group, treated between 1980-2000, and a late group, treated from 2001-2009. The relationship between the chronological treatment period and surgical outcomes, various histopathological factors, long-term outcomes, and recurrence patterns was investigated in this study. There were 295 men and 77 women. The mean (SD) age was 61.5 (9.7) years. Underlying liver diseases included cirrhosis in 203 patients (54.6%) and non-cirrhosis in 169 patients (45.4%). According to Child's classification, modified by Pugh et al. (9), 361 patients (97.0%) were grouped in class A, nine (2.4%) in B, and two (0.5%) in C. The mean (SD) tumor diameter was 4.1 (3.0) cm. Hepatectomy and tumor location were defined according to the classification of Couinaud's definition (10) of liver segmentation.
Treatment. Preoperative TACE was performed in 151 patients. The indications for hepatectomy and the type of operative procedure were usually determined based on patients' liver function, mainly assessed by the Makuuchi Criteria, which comprise of preoperative measurements of ascites, serum bilirubin levels, and the indocyanine green retention rate at 15 minutes (ICGR15) (11). Preoperative portal vein embolization was performed in four patients to prevent postoperative liver insufficiency. In total, 294 patients underwent anatomical resection, and 78 underwent non-anatomical resection.
Pathological examination. All resected liver specimens were cut at a thickness of approximately 5 mm, and the microscopic sections were viewed after staining with hematoxylin and eosin. The pathological diagnosis and classification of resected HCC tissues were performed according to the General Rules for the Clinical and Pathological Study of Primary Liver Cancer. (12) Tumors were staged using the definition of TNM classification by the International Hepato-Pancreato-Biliary Association and the International Union Against Cancer (UICC) (13).
Follow-up. The patients were followed-up with hepatic ultrasonography, computed tomography, and the assessment of serum levels of alpha-fetoprotein (AFP) and protein induced by vitamin K absence II every 3-6 months. Disease-free survival (DFS) was defined as the interval between surgery and the date of the diagnosis of the first recurrence or the date of the last follow-up. Overall survival (OS) was defined as the interval between surgery and the date of death caused by HCC recurrence or the date of the last follow-up. The median follow-up duration was 50.3 months.
Treatment for the hepatic recurrence of HCC. Local treatment for the initial hepatic recurrence of HCC consisted of local ablation therapy and repeat hepatectomy. TACE was performed by the Seldinger technique (14), with iodized oil or gelatin sponge cubes as an embolus material and adriamycin (10-30 mg) and mitomycin C (10-20 mg) as anticancer drugs.
Analysis. We performed univariate analyses of the clinical and pathological factors that were potentially associated with OS. Survival was calculated using the Kaplan–Meier method and was compared between groups using the log-rank test. A multivariate analysis using the Cox hazard model was performed to identify for independent predictors of survival. A p-value <0.05 was considered to be statistically significant. All statistical analyses were performed using the SPSS for Windows 11.5 software program (SPSS, Chicago, IL, USA).
Results
A test for serum hepatitis B surface antigen was positive in 85 patients, and the antibody against hepatitis C was present in serum in 164 patients. One patient from the early group died within 30 days of the operation because of acute renal failure. The cumulative 5-year OS and 5-year DFS rates of a total of 372 patients were 58.3% and 31.3%, respectively.
Table I shows a comparison of patients characteristics, surgical outcomes, and pathological characteristics between the early and late groups. In the host-related factors, the age of the patients in the late group was significantly greater than in the early group (p<0.001). Liver cirrhosis was significantly less frequent in the early group than in the late group (46% vs. 59%, p=0.015). Additionally, parameters of liver function, such as serum albumin (p<0.001), platelet count (p=0.031), and ICGR15 (p=0.007), were significantly better in the late group than in the early group. For treatment-related factors, the proportion of patients who underwent preoperative TACE (p<0.001) and anatomical resection (p<0.001) were significantly higher in the early group. The amount of blood loss (p<0.001) and the proportion of patients who underwent blood transfusion (p<0.001) were significantly higher in the early group. For the tumor-related factors, all pathological factors, including the UICC stage, were comparable between the groups. However, the preoperative AFP values were significantly higher in the early group than in the late group (p<0.001). There were no significant differences in DFS between the early and late groups (5-year DFS: 30.3% vs. 31.2%, p=0.526, Figure 1a). In contrast, the OS of the early group was significantly better than the OS of the late group (80.1% vs. 50.4%, p<0.001, Figure 1b).
Table II shows the results of the univariate and multivariate analyses of the prognostic factors associated with OS of the patients who underwent hepatectomy for the treatment of HCC. The Cox proportional hazard analysis identified serum albumin <3.5 g/dl (p=0.012), AFP >100 ng/ml (p=0.001), preoperative TACE (p=0.013), the presence of multiple tumors (p=0.001), infiltrating growth (p=0.035), liver cirrhosis (p<0.001), a tumor size ≥30 mm (p=0.013), and being in the early group of the chronological treatment period (p=0.007) as independent prognostic factors for poorer OS.
Figure 1c shows the comparison of the OS curves after initial hepatic recurrence according to different treatment modalities for the initial hepatic recurrence of HCC. OS in patients who underwent repeat hepatectomy after initial recurrence was significantly better than that in the patients who underwent TACE (5-year OS after initial recurrence: 44.6% vs. 24.8%, p=0.044). However, OS in patients who underwent local ablation therapy after initial recurrence was comparable with that of the patients who underwent TACE (5-year OS after initial recurrence: 33.1% vs. 24.8%, p=0.775).
Comparison of the characteristics of the patients who underwent hepatectomy for the treatment of hepatocellular carcinoma between the early (1980-2000) and the late (2001-2009) groups.
Table III shows the comparison of patient status after liver resection for the treatment of HCC between the early and late groups. The frequency of recurrence was significantly higher in the early group than in the late group (71% vs. 55%, p<0.001). The proportion of patients who underwent TACE to treat the initial recurrence of HCC was comparable between the early and late groups (65% vs. 68%, p=0.651). The proportion of patients who underwent repeat hepatectomy for the treatment of initial recurrence of HCC was lower in the late group than in the early group (8% vs. 17%, p=0.061). Additionally, the proportion of patients who underwent local ablation therapy was higher in the late group than in the early group (17% vs. 9%, p=0.064).
Figure 2a shows the comparison of the OS curves after initial recurrence according to the chronological treatment period. The 5-year OS after initial recurrence of 155 patients in the early group who experienced initial recurrence was 21.8%, and that of 65 patients in the late group with a similar experience was 45.2%, and there were significant differences between the groups (p<0.001). Moreover, we compared the survival after initial hepatic recurrence between the early and late groups for each treatment procedure for initial hepatic recurrence. Among the 56 patients who underwent local treatment including repeat hepatectomy and local ablation therapy for the initial hepatic recurrence of HCC, there were no significant differences in OS after initial recurrence between the early and late groups (5-year OS after initial recurrence: 36.6% vs. 49.4%, p=0.080, Figure 2b). In contrast, among the 144 patients who underwent TACE for treatment of the initial hepatic recurrence of HCC, the OS of the patients in the late group was significantly better than that of the early group (5-year OS after initial recurrence: 41.7% vs. 19.8%, p=0.002, Figure 2c).
Results of the univariate and multivariate analyses of the prognostic factors associated with overall survival in the patients who underwent hepatectomy for treatment of hepatocellular carcinoma.
Comparison of patient status after hepatectomy between the early (1980-2000) and the late (2001-2009) groups.
Discussion
Hepatic resection for the treatment of HCC is now a safe procedure with long-term outcomes as a result of improved surgical and peri-surgical care over the past decade. Three previous reports have emphasized on the significantly improved long-term outcomes of liver resection in patients with HCC by comparing patient groups from two time intervals (3, 4, 15). Our analysis also revealed improved long-term survival rates throughout the 21st century compared with the rates in the previous two decades, and for patients being in the early group of the chronological treatment period was an independent prognostic factor of poorer OS. In contrast, DFS was comparable between the early and late groups. These results suggest that the prognosis of HCC has been improving through the use of various combination therapies. However, hepatectomy is limited in its ability to prevent intra-hepatic metastasis and reduce the frequency of multicentric carcinogenesis (2, 5), even though the safety of liver resection has dramatically improved.
The long-term results of TACE tend to improve yearly. A Japanese nation-wide study of 9,363 patients who underwent TACE without lipiodol from 1980-1993 found a 5-year OS of 9% (16), whereas the 5-year OS of 8,510 patients who underwent TACE from 1994-2003 was 26% (17). In the present study, among the 144 patients who underwent TACE for treatment of the initial hepatic recurrence of HCC, the OS of the patients in the late group was significantly better than that in the early group (5-year OS after initial recurrence; 41.7% vs. 19.8%, p=0.009). The marked improvement of survival in recent years might partially depend on lead-time bias (18, 19). However, the recent improvement of survival after TACE may also be due to the introduction of lipiodol (20) and the technique of super-selective catheterization using a microcatheter system (8). Moreover, the incidence of TACE-related deaths has tended to decrease yearly (21). These improvements in the methodology of TACE have resulted in the improvement of long-term survival after the initial recurrence of HCC.
Repeat hepatectomy has been recognized as the most effective treatment for recurrent HCC in eligible patients, with 5-year survival rates ranging from 37-87% (22-24). In the present study, the 5-year survival rate of the patients who underwent repeat hepatectomy for the treatment of recurrent HCC was 44.6%, which is significantly better than that of patients who underwent TACE for the treatment of recurrent HCC. This difference in survival may be partially caused by patient selection bias (25). However, this finding suggests that repeat hepatectomy is an acceptable treatment option for HCC recurrence in selected patients.
The rate of patients who underwent a repeat hepatectomy decreased in the 21st century, whereas the rate of local ablation therapy increased. Local ablation methods have been applied as minimally-invasive alternatives to surgery in patients with small recurrent HCC. Recent studies have revealed that percutaneous local ablation therapy provides adequate local control of small HCC with an efficacy comparable to that of surgical resection in the long term (26, 27). However, no definitive conclusion can be drawn from the currently limited number of cases. It is imperative that a randomized controlled trial be conducted to clarify for optimal treatment selection in patients with intrahepatic recurrence.
Along with being in the early group of the chronological treatment period, serum albumin <3.5 g/dl, liver cirrhosis, AFP ≥100 ng/ml, the presence of multiple tumors, an infiltrating growth pattern, a tumor size ≥30 mm, and preoperative TACE were significant prognostic factors related to poorer OS in the current study. The first six parameters are related to liver function and HCC stage, which were previously mentioned as important prognostic factors (2, 15, 28). In contrast, several retrospective studies have demonstrated the efficacy of preoperative TACE, whose survival benefit was found to be controversial (29, 30). Certain randomized trials have been conducted to assess the clinical efficacy of preoperative TACE and have failed to show a positive effect (31-33). In our study, preoperative TACE was an independent prognostic factor of poorer OS, and we cannot recommend this treatment as a routine procedure before hepatectomy in patients with resectable HCC.
The cumulative disease free survival (DFS) (a) and overall survival (OS) (b) of the early (1980-2000) and late (2001-2009) groups, and the comparison of the OS curves after initial hepatic recurrence according to the different treatment modalities for the initial hepatic recurrence of hepatocellular carcinoma (c). LR: Liver resection, LA: Local ablation therapy, TACE: transarterial chemoembolization.
The blood transfusion requirement was significantly reduced in the late group in comparison with the early group. The results of hepatectomy have improved due to various developments in surgical methods and modalities (34). Homologous transfusions carry a poor prognosis (35) in addition to risks of infectious and immunological complications. Moreover, blood loss was reported to significantly correlate with long-term prognosis (36). Thus, it is important to reduce intra-operative blood loss and blood transfusion in patients with HCC. Further minimization of transfusion may also help to improve outcomes.
One of the limitations of the present study was its retrospective nature and single-center experience and the fact that the follow-up times for the early and late groups were different. Moreover, a lead-time bias was present because of recent advances in diagnostic modalities (18, 19, 37). However, we believe that the prognosis of HCC has been improving in the 21st century through use of various combination therapies, although the prognosis is still unsatisfactory.
Comparison of the overall survival (OS) curves after initial recurrence according to the chronological treatment period (a), and in the early and late groups among the 56 patients who underwent local treatment including repeat hepatectomy and local ablation therapy (b) and the 144 patients who underwent TACE (c) for treatment of the initial hepatic recurrence of hepatocellular carcinoma.
In conclusion, this study demonstrates that the results of liver resection for the treatment of HCC have improved over time due to the improvement of survival by various combination therapies after initial HCC recurrence. Repeat hepatectomy is an acceptable treatment option for HCC recurrence in selected patients.
- Received August 3, 2013.
- Revision received September 30, 2013.
- Accepted October 1, 2013.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
References
In this issue
Jump to section
Related Articles
Cited By...
- Prognostic Value of Repeat Hepatectomy for Hepatocellular Carcinoma Patients
- Prediction of Portal Vein Thrombosis Following Hepatectomy for Perihilar Cholangiocarcinoma: Efficacy of Postoperative Portal Vein Diameter Ratio and Angle
- The Radiological Differentiation of Hypervascular Intrahepatic Cholangiocarcinoma from Hepatocellular Carcinoma with a Focus on the CT Value on Multi-phase Enhanced CT